Osteoporosis is a bone disorder characterized by the loss of bone mass, which leads to fragility and porosity of the bone of man. As a result patients suffering from osteoporosis have an increased fracture risk of the bones. Especially in postmenopausal women osteoporosis is one of the major syndromes, resulting from the reduction of estrogen production by the ovaries. In general, the loss of bone in postmenopausal women is prevented or treated by estrogen replacement: when administered at low levels, the estrogens have a beneficial effect on the loss of bone. However disadvantages of the so called estrogen replacement therapy are the unwanted side effects of estrogens on the endometrium, i.e. the increased risk of breast carcinomas and endometrium stimulation and/or hyperplasia, resulting in the increased risk of endometrium carcinomas.
In the light of these serious side effects there is a strong need for an alternative treatment of osteoporosis, in which the use of estrogens is avoided. It is an object of the invention to provide for such alternative and safer routes for the prevention and/or treatment of osteoporosis.
The bone morphogenetic proteins (BMPs) are a group of proteins that can induce de novo cartilage and bone formation, and appear to be essential for skeletal development during mammalian embryogenesis (Wang, Trends Biotechnol. 11, 379, 1993). Due to their osteoinductive properties the BMPs can be of clinical interest. Recently, it has become evident that early in the process of fracture healing the concentration of bone morphogenetic protein-4 (BMP-4) increases dramatically (Nakase et al., J. Bone Miner. Res. 9, 651, 1994 and Bostrom et al., J. Orthopaed. Res. 13, 357, 1995). In vivo experiments show that upregulation of BMP-4 transcription indeed promotes bone healing in mammals (Fang et al., Proc. Natl. Acad. Sci. USA. 93, 5753, 1966). These observations suggest an important role of BMP-4 in bone remodeling and fracture repair.
Although the role of BMP-4 seems to be crucial during many stages of development, the regulatory mechanisms underlying the specific expression of the BMP-4 gene are unknown. BMP-4 transcripts are expressed in several specific tissues, shown by Northern blot analysis and in situ hybridization. Two human BMP-4 transcripts have been identified, which are completely identical in their coding region, but are different in their 5' non-coding regions. Previous investigations showed a cell line dependent expression of both transcripts. Interestingly, the presence of multiple transcripts suggested an important difference in BMP-4 gene regulation. Furthermore, the short half life of BMP-4 mRNA suggests that the gene is primarily regulated at transcriptional level (Rogers et al., Cell. Growth. Differ. 7, 115, 1996).